||Nucleoside Analogues: Future of Chemotherapeutic Agents
P. Merino, T. Tejero, F.L. Merchan, S. Franco, P. Romero, J.A. Matés, V. Mannucci
Bioorganic Chemistry Research Group
In the therapy of infections caused by viruses and also in
the treatment of certain neoplastic diseases, nucleoside analogues have emerged
as major chemotherapeutic agents. Since the discovery that nucleoside analogues
can effectively protect cells from the lethal action of some viruses, including
the human immunodeficiency virus (HIV), herpes simplex virus, hepatitis C virus
and cytomegalovirus, among others, several reviews have appeared concerning
their synthesis, therapeutic applications and mechanism of action. The majority
of nucleoside analogues consist of modifications of natural substrates in the
heterocyclic base or the sugar moiety. The general structure of a nucleoside
analogue is well-defined by three key elements: i) the hydroxymethyl group,
which is needed for activation through phosphorylation by kinases, ii) the heterocyclic
base, which is needed for the recognition by the enzymes and the complementary
strand in the nucleic acid synthesis process, and iii) the spacer, (the furanose
ring in natural compounds) which present the two former groups in the adequate
disposition. In this respect, it is interesting to speculate that the biological
effects exhibited by nucleoside analogues depend importantly on the relative
disposition of the hydroxy methyl group and the base moiety.
Figure 1. General structure of
Due to the high specifity of 5'-phosphorylating kinases only
a few variations are allowed regarding the hydroxymethyl group. There are a
vast family of compounds grouped under the name of nucleoside antibiotics that
present complex side chains instead of the hydroxymethyl group. Hydrogen bond
interactions of heterocyclic bases are fundamental for the biological activity
of nucleoside analogues. So, any variation of the base moiety should preserve
such intramolecular forces. As a consequence, only minor variations of bases
are found in biologically active nucleoside analogues. The most notable of that
sort of structural modifications is found in C-nucleosides, in which the typical
C-N glycosidic bond has been replaced by a non-hydrolizable C-C bond.
On the other hand, numerous variations are possible for the
spacer whilst still retaining activity. The relative 1',4' disposition of the
hydroxymethyl group and the heterocyclic base can also be modified in order
to obtain the so-called isonucleosides, compounds from both D- and L- enantiomeric
series that have shown antiviral activities.
The structural modifications of the spacer backbone also led
to active compounds. Replacement of the furanose ring by an acyclic chain, which
can adopt a conformation similar to conventional nucleosides, gives rise to
the acyclonucleosides, from which acyclovir, gancyclovir and their prodrugs
are the best known. The furanose ring can also be replaced by a different carbo
or heterocyclic ring. The carbocyclic analogues are also relevant compounds.
Pyranosyl nucleoside analogues have also been proposed an alternative to conventional
nucleosides in oligonucleotide chains. The corresponding analogues having a
four-membered ring (oxetane) instead the conventional furanose ring have also
Figure 2. Antiviral drugs
The interest in nucleoside analogues in which the furanose
ring is replaced by a different heterocyclic ring (heterocyclic nucleosides)
has appeared much more recently. It is the aim of the group of Bioorganic Chemistry
to study and develop the methodologies for the construction of those novel nucleoside
More complex nucleosides such as polyoxins and nikkomycins
are also studied in our group.
In particular, the polyoxins are a group of peptidyl nucleoside
antibiotics produced in the fermentation broth of Streptomyces cacaoi var
asoensis and that have been isolated and characterized by Isono and
co-workers about thirthy years ago. In total, about fifteen compounds having
closely related structures have been identified and designated with alphabetical
letters. Their structure showed the presence of a unique ribofuranosyl a -amino
acid nucleoside that constitutes the common skeleton to all of the members of
the family. The nucleoside portion that eventually bears different pyrimidine
bases is connected through amidic bonds to an open chain polyalkoxy a -amino
acid and to an azetidine-2-carboxylic acid. This tripeptide structure is illustrated
by the first member of the family, polyoxin A. Some polyoxins however are simply
dipeptides incorporating in their structure only two of the above amino acids.
This is the case of polyoxin J that in fact by hydrolytic degradation leads
to the polyalkoxy a -amino acid 5- O -carbamoyl-polyoxamic acid and
the amino acid nucleoside thymine polyoxin C.
Figure 3. General structure of Polyoxins
The original interest for polyoxins and the closely related
natural products nikkomycins and neopolyoxins as well as their synthetic analogues
stemmed from their marked activity against phytopathogenic fungi whereas are
non toxic to bacteria, plants, or animals. These biological effects apparently
are due to the ability of polyoxins to inhibit the enzyme chitin synthase and
therefore to prevent the biosynthesis of chitin, an essential component of the
fungal cell wall structure. Hence, the polyoxin complex obtained by fermentative
processes proved to be an excellent agricultural fungicide of wide use, particularly
for the sheath blight disease of rice plant. More recently, considerable attention
to all the above families of peptidyl nucleosides antibiotics, especially nikkomycins
and neopolyoxins has been addressed as inhibitors of opportunistic fungal infections
by Candida albicans in immuno-compromised hosts, such as AIDS victims
and organ transplant patients.
Figure 4. Differences in the cell wall
of Candida Albicans upon treatment with polyoxins
From natural sources it is only possible to isolate typical
furanose-containing compounds whereas in order to improve the activity novel
analogues are needed. Due to the differences found in the biological activities
of polyoxins and nikkomycins when measured against the enzyme (chitin synthase)
and Candida albicans in culture it is of high interest to prepare new
analogues which could be more effective as anticandidal agents. In this regard
the Bioorganic Chemistry group of ICMA has also been paid attention to the synthesis
of structural analogues of polyoxins and nikkomycins.
Figure 4. Commercial sources of Polyoxins
In our laboratory is an ongoing program aimed at demonstrating
the versatility of chiral nitrones
and hydroxylamines as building blocks for the efficient construction
of biologically interesting nitrogenated compounds. In particular, we are interested
in the synthesis of isoxazolidinyl nucleosides, the class of nucleoside analogues
in which the furanose ring has been replaced by an isoxazolidine ring. Our experience
in Organic Synthesis allows us to suggest that isoxazolidinyl nuleoside analogues
of complex nucleosides can be synthesized by applying our nitrone-based methodology.
Thus our goal is to design novel isoxazolidinyl analogues of both conventional
nucleosides and complex nucleosides including nucleoside antibiotics such as
polyoxins and nikkomycins.
We thank for their support the Ministry of Science and Technology
(MCYT, Spain) and FEDER Program (Project CASANDRA, BQU2001-2428) and the Government
of Aragon (Project P116-2001).
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